Decreased RBC production may occur when the bone marrow is not functioning normally. This can result from a bone marrow disorder such as aplastic anemia. Diminished production can also be due to other factors, for example, cirrhosis of the liver, kidney disease, radiation or chemotherapy treatments for cancer, a low level of the hormone erythropoietin, or deficiencies in certain nutrients such as iron, vitamin B12, or folate. Decreased production leads to fewer RBCs in circulation, decreased hemoglobin and oxygen-carrying capacity, a lower hematocrit, and a reduced number of reticulocytes as old RBCs are removed from the blood but not fully replaced.

Occasionally, both the reticulocyte count and the RBC count will be increased because of excess RBC production by the bone marrow. This may be due to an increased production of erythropoietin, disorders that cause chronic overproduction of RBCs (polycythemia vera), and cigarette smoking.

Acute or chronic bleeding (hemorrhage) or increased RBC destruction (hemolysis) can lead to fewer RBCs in the blood, resulting in anemia. The body compensates for this loss or to treatment of deficiency anemias (such as iron deficiency anemia or pernicious anemia) by increasing the rate of RBC production and by releasing RBCs sooner into the blood, before they become more mature. When this happens, the number and percentage of reticulocytes in the blood increases until a sufficient number of RBCs replaces those that were lost or until the production capacity of the bone marrow is reached.